Cancer is a category of severe diseases affecting human health, and its treatment is becoming a huge and imminent public issue awaiting more effective therapies. Although much progress has been made recently in anticancer drug research, the unfavorable specificity and harmful side effects to normal cells limit their applications. Therefore, genetic engineering drugs for targeted cancer therapy are still well welcomed due to potential social and economic benefits.
In 1995, Wiler S R et al. reported the finding of a new gene from expressed sequence tag (EST) library coding for a new antitumor protein, human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or Apo2L), belonging to the Tumor Necrosis Factor superfamily (Wiley S R, et al., Immunity 3:673-682, 1995). After TRAIL binding to DR4 or DR5, the death domains of the receptors pass the apoptosis signaling through FADD and caspase 8. TRAIL inhibits the growth of and is cytotoxic to most malignant cancer cell lines, however, normal cells are largely refractory to its apoptotic cytotoxicity (Ashkenazi A, et al., J Clin Invest 104:155-162, 1999). Because of its specific apoptotic activity against cancer but not to normal cells, TRAIL holds great promises in anticancer treatment and has been a hot research spot. Although TRAIL has demonstrated significant in vitro and in vivo as well as clinical tumor-inhibitory activities, its half life is relatively short, with a T1/2 of about 40 minutes in human, seriously compromising its in vivo efficacy.